We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.

Since 1997, the Research Department of the French Ministry of Ecology and Sustainable Development (MEDD) supports research programmes dealing with flood risk evaluation and management. These programmes aim for making science in support to policy making. They complete operational studies which are supported mainly by two other Directions of the Ministry (Water Direction; Risk and Pollution Prevention Direction). A rapid view of the programs which are supported by MEDD is given and an analysis is done. Some remarks and analysis are suggested.

IRSN (France) and SCK-CEN (Belgium), two institutes of research and expertise in radiation protection and nuclear safety, simultaneously organised a very similar public opinion survey in their respective countries in November 2002. The study explores subjects such as: major people's concerns, perception of environmental risks, perception of risks in general, the role of experts in decision making, opinions on nuclear matters and aspects of nuclear emergency preparedness. In each country, more than 1000 citizens representing the general public have been consulted in face-to-face interviews. The field work has been performed by professional companies (BVA in France and Research International in Belgium). The paper shows that industrial and technological risks are not perceived as one of the major public concerns, although many other risks, of different nature are considered to be high. The actions of the authorities to provide protection against the consequences of many risks or disasters are not considered to be sufficient, and many respondents claim not to believe the information they receive. There exists a large difference between the opinion of French and Belgian public, and within the different language groups in Belgium, with regard to who should be in charge of the control of the hazardous industries. Many of the "actors" within the nuclear industry are not known by the respondents. The perception of the technical competence or the truth being told shows large variations between the main actors (such as members of the nuclear industry, the government or the media). Majorities within the population believe that a disaster as serious as the Chernobyl one can happen in their country and that in case of a nuclear accident, the authorities would not be capable to protect the population adequately.

Two experiments studied the frequency pattern of TLS (temporary loudness shift) as a function of the level and frequency of the fatiguing sound. In experiment 1, the fatiguing tones were intermittent 375-, 1500-, or 3000-Hz tones (10 s on/10 s off) at 75, 80, 85, 90, or 95 dB SPL. The TLS patterns were established for a continuous, 60-phon test tone at different frequencies presented simultaneously with the intermittent fatiguing tone. In experiment 2, a 1000-Hz exposure tone with an intermittency of 10 s on/20 s off was used with a continuous 60-dB test tone at different frequencies. In both experiments, the total exposure duration was 60 s; TLS was measured 5 s after the exposure ended. For the lowest two exposure levels, the TLS pattern had one peak centered on the exposure frequency. As the exposure level increased, a two-peak pattern became evident, with the second peak at higher test frequencies. This finding could be interpreted as psychoacoustical evidence for the double (passive and active) mode of displacement of the basilar membrane. In experiment 2, a TTS (temporary threshold shift) measurement after exposure to a 45-min, 1000-Hz tone at 90 dB was added to the TLS sessions. The correlations between maximum TTS after a 45-min exposure and the TLS obtained after a 60-s exposure were calculated for each of the exposure levels and test frequencies used in TLS measurements. The correlation reached as high as 0.9 for TLSs measured at 1120 Hz after a 90-dB exposure; it was smaller but significant for TLSs at the exposure frequency. Despite these correlations, differences in the overall patterns of TTS and TLS suggest that they stem from two different mechanisms.

An intermittent monaural tone may induce a decline in the loudness of a continuous tone presented to the same ear [Canévet et al., Br. J. Audiol. 17, 49–57 (1983)]. Two experiments studied the frequency selectivity of loudness adaptation induced in this manner. The method of successive magnitude estimations was used to measure the loudness of a monaural 84-s test tone before and after a single presentation of a 24-s inducer tone in the same ear. The first experiment shows that, for an inducing tone (500, 1000, or 3000 Hz) approximately 15 dB more intense than a test tone set to one of 21 different frequencies, adaptation is greatest when the two tones have the same frequency; with increasing difference between the test-tone and inducer frequencies, adaptation progressively declines. The second experiment measured frequency selectivity in the loudness reduction caused by a 1000-Hz inducer as a function of its level. As inducer level went from 75 to 95 dB (with test tone constant at 60 phons), selectivity passes progressively from the type seen in short-term or low-level fatigue (maximal for the 1000-Hz test tone) to a type seen in long-term or high-level fatigue (maximal at frequencies higher than that of the inducer or fatiguing tone). A common cochlear origin and a continuity between the mechanisms of ipsilaterally induced adaptation and high-level fatigue are suggested by the data.

Measurements of induced loudness adaptation and temporary threshold shift (TTS) were made on 48 young subjects. Loudness adapatation of a continuous 60-dB test tone was induced in the right ear by an intermittent 1000-Hz inducer tone at 90 dB, presented every 30 s for 20 s. The loudness of a 1000-Hz or 1160-Hz test tone at 60 dB was measured after each occurrence of the inducer by the method of successive magnitude estimations. Induced adaptation caused the loudness of the continuous tone to decrease on the average by 38% (the equivalent of 14 dB) after 120 s. In a separate session, the subject's right ear was exposed for 45 min to a 1000-Hz tone at 90 dB SPL. One minute after exposure, thresholds were measured by Békésy tracking for 4 min. The maximum TTS, averaged across subjects, was 20.4 dB at a mean frequency of 1635 Hz. The correlation between maximum TTS and the amount of induced adaptation was 0.83. Thus ipsilaterally induced adaptation (IIA), which is akin to temporary loudness shift, may stem from cochlear mechanisms just as TTS does. Also, IIA could become the basis for an audiological test to identify those individuals most susceptible to auditory fatigue. [Work supported by Ministère de l'Environnement and NIH.]